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1
Combination Products: A Regulatory Perspective
Kathy Lee, M.S. Associate Chief, Laboratory of Biochemistry
DTP/OPB/OPS/CDER/FDA WCBP 2012
2
Outline • Combination Products • Jurisdiction • Regulatory Challenges • Regulations/Guidance for Industry • Human Factor Studies • Comparability • Case Studies
4
Prefilled Syringes • In 2005 the worldwide market for pre-filled
syringe was ~ 1 billion units in 2010 that number has increased to over 2 billion units
• The growth of the market is anywhere from 12.5% to 20% yearly.1
1Ondrugdelivery.com 2005
5
Prefilled Syringes • Advantages
– Ease of administration • Easier for patients to use at home or in emergency
situations – Prefilled dosage reduces medication errors – Elimination of vial overfill – Greater assurance of sterility – Cost
6
Prefilled Syringes • Disadvantages
– Technical challenges for developing and manufacturing
• Silicone • Aggregates • Leachable and Extractable
– Regulatory challenges – Greater cost of development
8
Who Has Jurisdiction? • Governed by Primary Mode of Action (PMOA)
– 21 CFR 3.2m
– Primary mode of action is the therapeutic action that is expected to make the greatest contribution to the overall intended therapeutic effect of the combination product.
– Whichever product has the greatest therapeutic effect, the center that the product is regulated in will have jurisdiction.
9
Who Has Jurisdiction? • Drug eluting stent - CDRH - PMOA is the stent
opening the artery
• Drug eluting disks - CDER - PMOA is the cancer chemotherapy
• Bone graft substitutes – CDRH and CDER – CDRH lead – PMOA is spinal or fracture stabilization – CDER lead – device component acts as drug delivery
system
10
Request for Designation (RFD) • 21 CFR 3.7 • Ask for classification (biologic/device) and
Center lead assignment – Primary mode of action (PMOA) – Similarity to other regulated products – Center with most experience/expertise
• Fully voluntary • Guidance Document: How to Write a Request
for Designation
11
Request for Designation (RFD) • The request is submitted to the Office of
Combination Products (OCP) – Each center will review the RFD and write a
short memo agreeing or disagreeing with the sponsor
– OCP will make final determination
• FDA has 60 days to make the decision
12
Office of Combination Products • Mandated by the Medical Device User Fee and
Modernization Act of 2002 (MDUFMA)
• Works with industry and CBER, CDER and CDRH
• Make jurisdictional determinations
• Oversee/help coordinate premarket review and ensures consistent/appropriate postmarket regulation
• Develops policy, guidance and regulations
• Serve as resource for industry and review staff
13
Combination Products By the Numbers
• Total of 311 submitted to the Agency in 2010 (latest data)
• Highest percentage are INDs and 510Ks
• 32 RFD were assessed http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/PerformanceReports/
CombinationProducts/UCM270772.pdf
15
General Regulatory Differences • Each Center has a different set of laws
and regulations acting as the basis for its authority – Food, Drug and Cosmetic Act
• Drugs and Devices – Public Health Services Act
• Biologics – Code of Federal Regulations (21 CFR)
• 314 Drug • 600 Biologics • 800 Device
16
General Regulatory Differences
• Any available laws or regulations may be applied as necessary and appropriate for regulation of specific combination product – This will change as new regulations are
promulgated
17
General Regulatory Differences
• Least Burdensome provisions of the FDA Modernization Act do not apply to the complete combination product – only apply to the device component(s)
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General Regulatory Differences Each Center is organized differently
clinical pharm/tox CMC manufacturing
manufacturing and compliance
device issues clinical
pharm/tox CMC
compliance
CDER/CBER
CDRH
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Specific Regulatory Differences
• Electronic submissions • Meetings • Clinical studies • Non-clinical studies • Marketing applications • Manufacturing and compliance
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Electronic Documents • CDER/CBER
– electronic submissions generally required – accessible by CDRH
• CDRH – optional electronic submissions – accessible by CDER/CBER
21
Regulatory Meetings • CDER/CBER
– Type A, B or C – Formal processes – 30, 60, 75 day
• CDRH – pre-submission
• informal • 60 day clock
– “regular” request • informal • first available date
– Agreement • formal • 30 day clock
22
Clinical Studies: CDER/CBER • Investigational New Drug (IND)
– Phase 1 • Primarily Safety and to determine pharmacologic and
metabolic activity and side effects • Exempt from CGMPs
– Phase 2 • Often dose-finding studies • Study efficacy in a limited group of individuals
– Phase 3 • Used to evaluate overall benefit-risk relationship of the drug • Provide adequate basis for physician labeling
• Clinical Hold
23
Clinical Studies: CDRH • Investigational Device Exemptions (IDE)
– Feasibility – pilot – pivotal – Exempt from QSRs
• Number of required studies product-dependent • No direct mapping to IND phases • No concept of clinical hold • Need to demonstrate “relative safety” prior to
initiation • Max 30 day review cycle
24
Non-Clinical Studies • Types of data is the same between Centers but
the timing of data and conditions for initiating clinical trials are different
• CDER/CBER – specific upfront data submission with commitments
for subsequent data submissions during studies • CDRH
– all necessary data submitted upfront as part of “relative safety” demonstration
– usually no additional data submitted after approval
25
Original Applications Lead Center Application Type Review Clock
CDER/CBER LEAD New Drug Application or
Biologic License Application
6 Month (Priority Review)
Or 10 Month (Standard Review)
CDRH
Pre Market Approval
180 Day
510K premarket notification
90 Days
HDE humanitarian device
exemption
75 Days
26
Manufacturing Changes: Post Licensure
• Changes to Manufacturing Process • New Facility • Changes to Sterilization • Extension of Expiration Date • Changes in Equipment, Raw Materials,
New Master or Working Cell Bank • Change in Methods • Change in device design
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Manufacturing Changes: Post Licensure
• CDER/CBER – 21 CFR 314.70 – 21 CFR 601.12
• CDRH – 21 CFR 814.39(a) – 21 CFR 814.39(b) – 21 CFR 814.39(f)
28
Manufacturing Supplements
Lead Center Manufacturing Supplement Review Clock
CDER/CBER LEAD
Prior Approval 4 Months
Changes Being Effective 6 Months
Annual Report 1 Year
29
Manufacturing Supplements
Lead Center Manufacturing Supplement Review Clock
CDRH
PMA Supplement 180 Days 30-Day Notice and
135-Day PMA Supplement
30 Days or 135 Days
Annual Report 90 Days
HDE Supplement 30 Days or 75 Days
31
Manufacturing Practices
• Which should you follow? – There are currently no CGMPs/QS regulations for
combination products
– Each constituent part (drug, device or biologic) will be regulated under their cGMP/QSR requirements when manufactured separately and later combined
– For combination products produced as a single-entity or co-packaged both sets of cGMP/QS regulations are applicable
32
Manufacturing Practices
• Draft Guidance for Industry: Current Good Manufacturing Practice for Combination Products (2004)
• Manufactures of combination products should meet with the FDA and discuss how the CGMP/QSR requirements apply to their product throughout product development
36
Proposed 21 CFR 4 • Subpart A – Current Good Manufacturing
Practice Requirements for Combination Products – The proposed rule at 4.4(b) would offer two options
for demonstrating compliance with cGMP requirements for each of the constituent parts in co-packaged or single-entity combination product.
• (1) To demonstrate compliance with the specifics of all cGMP regulations applicable to each of the constituent parts
• (2) To demonstrate compliance with the specifics of either the drug cGMPs or the QS regulation, rather than both
37
Proposed 21 CFR 4 • 4.4(b)(1):
– If you follow the drug cGMP regulations at 21 CFR 210 and 211, you must also follow specific provisions of the QS regulation,
• § 820.20. Management responsibility • § 820.30. Design controls • § 820.50. Purchasing controls • § 820.100. Corrective and preventive action • § 820.170. Installation • § 820.200. Servicing
38
Proposed 21 CFR 4 • 4.4(b)(2)
– If you follow the drug QS regulations at 21 CFR 820, you must also follow specific provisions of the cGMP regulations
• § 211.84. Testing and approval or rejection of components, drug product containers, and closures
• § 211.103. Calculation of yield • § 211.132. Tamper-evident packaging for over-the-counter
(OTC) human drug products • § 211.137. Expiration dating • § 211.165. Testing and release for distribution • § 211.166. Stability testing • § 211.167. Special testing requirements • § 211.170. Reserve samples
39
Guidance for Industry • Guidance for Industry and FDA Staff - Early
Development Considerations for Innovative Combination Products (2006)
• FDA Guidance: Container Closure Systems for Packaging Human Drugs and Biologics (May 1999)
• DRAFT Guidance for Industry: Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products (2009)
• Variety of ISO standards are also useful
41
Human Factor Studies • Changing regulatory landscape
– These are now required instead of “nice to do” – Relying on controlled clinical studies will not
substitute for Human Factor Studies • Human Factor Premarket Evaluation
Team is part of CDRH Office of Device Evaluation – Collaborates with CDER’s Division of
Medication Errors Prevention and Analysis
42
Human Factor Studies • Guidance for Industry and FDA Staff: Medical
Device Use‐Safety: Incorporating Human Factors Engineering into Risk Management (2000)
• Draft Guidance for Industry and FDA Staff: Applying Human Factors and Usability Engineering to Optimize Medical Device Design (2011)
43
Human Factor Studies • Formative Usability Testing
– Identifies strengths and weaknesses – How can it be made better – Should be conducted while device is still under development – Iterative Process
• Summative Usability Testing – Final product testing – Tested by representative user under realistic conditions – Develop mitigation strategy for failures or problems that arise
• Modify the design interface • User instructions/training • Re-test to show effectiveness of mitigation
44
Most Common Human Factor/Usability Review Concern1
• HF/Usability work is needed but not provided • No HF/Usability work prior to summative/HF
Validation testing • Discovering new use‐related problems at this
point and “explaining them away” • Lack of effective follow up on residual risk and
performance failures • Related hazards not identified
1Adapted from Ron Kay, Molly Follette Story, QuynhNhu Nguyen FDA/CDRH/ODE September 20, 2011
45
Most Common Human Factor/Usability Review Concern1
• Inadequate or absent description or characterization of errors
• No systematic collection of subjective description by test participants
• Not testing with representative users of the intended population of users
• Testing and evaluation not clearly related to tasks
1Adapted Ron Kay, Molly Follette Story, QuynhNhu Nguyen FDA/CDRH/ODE September 20, 2011
47
Product Concerns • Consider how the product will be used in the
clinic – Length of mixing and holding time prior to implant
• Assess the key product quality attributes using release and characterization assays – Purity – Protein recovery – Specific activity – Glycosylation
• Understanding the interaction between the device and the biologic or drug
49
Comparability • Not uncommon for products to be developed
initially in vials (liquid/lyophilized) and then switched to prefilled syringes – Ideally the switch should occur prior to the pivotal
clinical studies – Need to demonstrate comparability between vials and
prefilled syringes • The extent of comparability is dependant on the phase of
development • Now subject to combination product regulations
50
Demonstration of Comparability
• Biocompatibility testing should be performed as described in Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing (May 1995)
• Need to determine if the current formulation is compatible with the prefilled syringe – Silicone can interfere with the protein or exicipients in
the drug product
51
Demonstration of Comparability • Demonstrate that the prefilled syringes do not
impact product quality using Release and Characterization tests – Potency – Purity – Aggregation – Include impurity profiles where applicable – Glycosylation – Deamidation – N-terminal truncation – Secondary, tertiary, quaternary structure
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Demonstration of Comparability • Conduct leachable and extractable studies for all
component materials for the device – Full description of extraction procedures should be described – Leached tungsten has been an issue for some proteins
• Comprehensive stability testing should be conducted in the prefilled syringes to establish expiration dating. – Bench testing for container closure and package ruggedness
should include • Mechanical reliability • Pressure changes • Vibrations • Temperature cycling and temperature extremes
– Shipping studies should be performed with the drug product in prefilled syringes
53
Demonstration of Comparability
• Preclinical or clinical studies may be required depending on the impact to product quality – The extent of preclinical or clinical studies depends
on phase of development
• Other Considerations – Human Factor studies – Confirm that all applicable regulations are being
followed
55
Case Study #1 • New IDE • Licensed Biologic with a new matrix • Matrix is a combination of a known material and
additional component • Sponsor performed elution studies
– Found the biologic was completely oxidized • Sponsor demonstrated that potency was not affected
• IDE was Disapproved • Did not provide data showing if other attributes may have
been impacted using release and characterization assays – Did not provide a rationale on why the oxidation occurred
56
Case Study #2 • Pre-filled Syringes
– Impact: tungsten salts caused protein oxidation followed by aggregation
– Up to 60% of aggregated product found in some syringes
• Resolution (different approaches were used by different Sponsors) – Optimal - switch to platinum instead of tungsten
filaments – Alternative – establish tungsten specifications,
nitrogen overlay process, special washing procedure, etc.
57
Summary • Regulation of Combination Products are complex • Identification of appropriate regulations is often difficult
and confusing but new regulations should be prorogated soon (target date: May 2012) to help eliminated the confusion
• Human Factor studies are required for prefilled syringes Important to study the impact the device has on the biologic/drug component
• Comparability studies not only include product impact but the impact of the product on the device
• Early contact/collaboration with the FDA is recommended to reduce development time and expenses